Triazolo-pyridazine derivatives as ligands for GABA receptors

ABSTRACT

1,2,4-triazolo[4,3-b]pyridazine derivatives, possessing an optionally substituted cycloalkyl, phenyl or heteroaryl substituent at the 3-position, a substituted alkoxy moiety at the 6-position, and an optionally substituted bicycloalkyl ring system at the 7-position, are selective ligands for GABA A  receptors, in particular having high affinity for the α2 and/or α3 subunit thereof, are useful in the treatment of anxiety and convulsions.

This is an application under 35 U.S.C. 371 of PCT/GB99/00063 and claimspriority from Great Britain Applications No. 9800752.9, filed Jan. 14,1998, and No. 9809204.2, filed Apr. 29, 1998.

The present invention relates to a class of substitutedtriazolo-pyridazine derivatives and to their use in therapy. Moreparticularly, this invention is concerned with substituted1,2,4-triazolo[4,3-b]pyridazine derivatives which are ligands forGABA_(A) receptors and are therefore useful in the therapy ofdeleterious mental states.

Receptors for the major inhibitory neurotransmitter, gamma-aminobutyricacid (GABA), are divided into two main classes: (1) GABA_(A) receptors,which are members of the ligand-gated ion channel superfamily; and (2)GABA_(B) receptors, which may be members of the G-protein linkedreceptor superfamily. Since the first cDNAs encoding individual GABA_(A)receptor subunits were cloned the number of known members of themammalian family has grown to include at least six α subunits, four βsubunits, three γ subunits, one δ subunit, one ε subunit and two ρsubunits.

Although knowledge of the diversity of the GABA_(A) receptor gene familyrepresents a huge step forward in our understanding of this ligand-gatedion channel, insight into the extent of subtype diversity is still at anearly stage. It has been indicated that an α subunit, a β subunit and aγ subunit constitute the minimum requirement for forming a fullyfunctional GABA_(A) receptor expressed by transiently transfecting cDNAsinto cells. As indicated above, δ, ε and ρ subunits also exist, but arepresent only to a minor extent in GABA_(A) receptor populations.

Studies of receptor size and visualisation by electron microscopyconclude that, like other members of the ligand-gated ion channelfamily, the native GABA_(A) receptor exists in pentameric form. Theselection of at least one α, one β and one γ subunit from a repertoireof seventeen allows for the possible existence of more than 10,000pentameric subunit combinations. Moreover, this calculation overlooksthe additional permutations that would be possible if the arrangement ofsubunits around the ion channel had no constraints (i.e. there could be120 possible variants for a receptor composed of five differentsubunits).

Receptor subtype assemblies which do exist include, amongst many others,α1β2γ2, α2β2/3γ2, α3βγ2/3, α2βγ1, α5β3γ2/3, α6βγ2, α6βδ and α4βδ.Subtype assemblies containing an α1 subunit are present in most areas ofthe brain and are thought to account for over 40% of GABA_(A) receptorsin the rat. Subtype assemblies containing α2 and α3 subunitsrespectively are thought to account for about 25% and 17% of GABA_(A)receptors in the rat. Subtype assemblies containing an α5 subunit areexpressed predominantly in the hippocampus and cortex and are thought torepresent about 4% of GABA_(A) receptors in the rat.

A characteristic property of all known GABA_(A) receptors is thepresence of a number of modulatory sites, one of which is thebenzodiazepine (BZ) binding site. The BZ binding site is the mostexplored of the GABA_(A) receptor modulatory sites, and is the sitethrough which anxiolytic drugs such as diazepam and temazepam exerttheir effect. Before the cloning of the GABA_(A) receptor gene family,the benzodiazepine binding site was historically subdivided into twosubtypes, BZ1 and BZ2, on the basis of radioligand binding studies. TheBZ1 subtype has been shown to be pharmacologically equivalent to aGABA_(A) receptor comprising the α1 subunit in combination with βsubunit and γ2. This is the most abundant GABA_(A) receptor subtype, andis believed to represent almost half of all GABA_(A) receptors in thebrain.

Two other major populations are the α2βγ2 and α3βγ2/3 subtypes. Togetherthese constitute approximately a further 35% of the total GABA_(A)receptor repertoire. Pharmacologically this combination appears to beequivalent to the BZ2 subtype as defined previously by radioligandbinding, although the BZ2 subtype may also include certain α5-containingsubtype assemblies. The physiological role of these subtypes hashitherto been unclear because no sufficiently selective agonists orantagonists were known.

It is now believed that agents acting as BZ agonists at 1βγ2, α2βγ2 orα3βγ2 subunits will possess desirable anxiolytic properties. Compoundswhich are modulators of the benzodiazepine binding site of the GABA_(A)receptor by acting as BZ agonists are referred to hereinafter as“GABA_(A) receptor agonists”. The α1-selective GABA_(A) receptoragonists alpidem and zolpidem are clinically prescribed as hypnoticagents, suggesting that at least some of the sedation associated withknown anxiolytic drugs which act at the BZ1 binding site is mediatedthrough GABA_(A) receptors containing the α1 subunit. Accordingly, it isconsidered that GABA_(A) receptor agonists which interact morefavourably with the α2 and/or α3 subunit than with α1 will be effectivein the treatment of anxiety with a reduced propensity to cause sedation.Also, agents which are antagonists or inverse agonists at al might beemployed to reverse sedation or hypnosis caused by α1 agonists.

The compounds of the present invention, being selective ligands forGABA_(A) receptors, are therefore of use in the treatment and/orprevention of a variety of disorders of the central nervous system. Suchdisorders include anxiety disorders, such as panic disorder with orwithout agoraphobia, agoraphobia without history of panic disorder,animal and other phobias including social phobias, obsessive-compulsivedisorder, stress disorders including post-traumatic and acute stressdisorder, and generalized or substance-induced anxiety disorder;neuroses; convulsions; migraine; depressive or bipolar disorders, forexample single-episode or recurrent major depressive disorder, dysthymicdisorder, bipolar I and bipolar II manic disorders, and cyclothymicdisorder; psychotic disorders including schizophrenia; neurodegenerationarising from cerebral ischemia; attention deficit hyperactivitydisorder; and disorders of circadian rhythm, e.g. in subjects sufferingfrom the effects of jet lag or shift work.

Further disorders for which selective ligands for GABA_(A) receptors maybe of benefit include pain and nociception; emesis, including acute,delayed and anticipatory emesis, in particular emesis induced bychemotherapy or radiation, as well as post-operative nausea andvomiting; eating disorders including anorexia nervosa and bulimianervosa; premenstrual syndrome; muscle spasm or spasticity, e.g. inparaplegic patients; and hearing loss. Selective ligands for GABA_(A)receptors may also be effective as pre-medication prior to anaesthesiaor minor procedures such as endoscopy, including gastric endoscopy.

In DE-A-2741763, and in U.S. Pat. Nos. 4,260,755, 4,260,756 and4,654,343, are described various classes of1,2,4-triazolo[4,3-b]pyridazine derivatives which are alleged to beuseful as anxiolytic agents. The compounds described in DE-A-2741763 andin U.S. Pat. Nos. 4,260,755 and 4,654,343 possess a phenyl substituentat the 6-position of the triazolo-pyridazine ring system. The compoundsdescribed in U.S. Pat. No. 4,260,756, meanwhile, possess a heteroarylmoiety at the 6- or 8-position. In none of these publications, however,is there any disclosure or suggestion of 1,2,4-triazolo[4,3-b]pyridazinederivatives wherein the substituent at the 6-position is attachedthrough a directly linked oxygen atom.

EP-A-0085840 and EP-A-0134946 describe related series of1,2,4-triazolo[3,4-α]phthalazine derivatives which are stated to possessantianxiety activity. However, there is no disclosure nor any suggestionin either of these publications of replacing the benzo moiety of thetriazolo-phthalazine ring system with any other functionality.

The present invention provides a class of triazolo-pyridazinederivatives which possess desirable binding properties at variousGABA_(A) receptor subtypes. The compounds in accordance with the presentinvention have good affinity as ligands for the α2 and/or α3 subunit ofthe human GABA_(A) receptor. The compounds of this invention mayinteract more favourably with the α2 and/or α3 subunit than with the α1subunit. Desirably, the compounds of the invention will exhibitfunctional selectivity in terms of a selective efficacy for the α2and/or α3 subunit relative to the α1 subunit.

The compounds of the present invention are GABA_(A) receptor subtypeligands having a binding affinity (K_(i)) for the α2 and/or α3 subunit,as measured in the assay described hereinbelow, of 100 nM or less,typically of 50 nM or less, and ideally of 10 nM or less. The compoundsin accordance with this invention may possess at least a 2-fold,suitably at least a 5-fold, and advantageously at least a 10-fold,selective affinity for the α2 and/or α3 subunit relative to the α1subunit. However, compounds which are not selective in terms of theirbinding affinity for the α2 and/or α3 subunit relative to the α1 subunitare also encompassed within the scope of the present invention; suchcompounds will desirably exhibit functional selectivity in terms of aselective efficacy for the α2 and/or α3 subunit relative to the α1subunit.

The present invention provides a compound of formula I, or a salt orprodrug thereof:

wherein

Y represents hydrogen or C₁₋₆ alkyl;

Z represents an optionally substituted C₆₋₈ bicycloalkyl moiety;

R¹ represents C₃₋₇ cycloalkyl, phenyl, furyl, thienyl or pyridinyl, anyof which groups may be optionally substituted; and

R² represents cyano(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, C₃₋₇cycloalkyl(C₁₋₆)alkyl, propargyl, C₃₋₇heterocycloalkylcarbonyl(C₁₋₆)alkyl, aryl(C₁₋₆)alkyl orheteroaryl(C₁₋₆)alkyl, any of which groups may be optionallysubstituted.

The groups Z, R¹ and R² may be unsubstituted, or substituted by one ormore, suitably by one or two, substituents. In general, the groups Z, R¹and R² will be unsubstituted or monosubstituted. Examples of optionalsubstituents on the groups Z, R¹ and R² include C₁₋₆ alkyl,aryl(C₁₋₆)alkyl, pyridyl(C₁₋₆)alkyl, halogen, halo(C₁₋₆)alkyl, cyano,cyano(C₁₋₆)alkyl, hydroxy, hydroxymethyl, C₁₋₆ alkoxy, C₃₋₇cycloalkyl(C₁₋₆)alkoxy, C₃₋₇ cycloalkoxy, amino(C₁₋₆)alkyl,di(C₁₋₆)alkylamino(C₁₋₆)alkyl, di(C₁₋₆)alkylaminocarbonyl(C₁₋₆)alkyl,N-(C₁₋₆)alkylpiperidinyl, pyrrolidinyl(C₁₋₆)alkyl,piperazinyl(C₁₋₆)alkyl, morpholinyl(C₁₋₆)alkyl,di(C₁₋₆)alkylmorpholinyl(C₁₋₆)alkyl and imidazolyl(C₁₋₆)alkyl.Representative substituents include C₁₋₆ alkyl, aryl(C₁₋₆)alkyl,halogen, cyano, hydroxy, hydroxymethyl, C₁₋₆ alkoxy and C₃₋₇cycloalkyl(C₁₋₆)alkoxy, especially C₁₋₆ alkyl or halogen.

As used herein, the expression “C₁₋₆ alkyl” includes methyl and ethylgroups, and straight-chained or branched propyl, butyl, pentyl and hexylgroups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl,tert-butyl and 1,1-dimethylpropyl. Derived expressions such as “C₁₋₆alkoxy” are to be construed accordingly.

Typical C₃₋₇ cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.

The expression “C₃₋₇ cycloalkyl(C₁₋₆)alkyl” as used herein includescyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl andcyclohexylmethyl.

Typical aryl groups include phenyl and naphthyl, preferably phenyl.

The expression “aryl(C₁₋₆)alkyl” as used herein includes benzyl,phenylethyl, phenylpropyl and naphthylmethyl.

Suitable heterocycloalkyl groups include azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl groups.

Suitable heteroaryl groups include pyridinyl, quinolinyl, isoquinolinyl,pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl,dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl,indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolylgroups.

The expression “heteroaryl(C₁₋₆)alkyl” as used herein includesfurylmethyl, furylethyl, thienylmethyl, thienylethyl, pyrazolylmethyl,oxazolylmethyl, oxazolylethyl, isoxazolylmethyl, thiazolylmethyl,thiazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl,oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl,thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl,tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyridazinylmethyl,pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl,isoquinolinylmethyl and quinoxalinylmethyl.

The term “halogen” as used herein includes fluorine, chlorine, bromineand iodine, especially fluorine or chlorine.

For use in medicine, the salts of the compounds of formula I will bepharmaceutically acceptable salts. Other salts may, however, be usefulin the preparation of the compounds according to the invention or oftheir pharmaceutically acceptable salts. Suitable pharmaceuticallyacceptable salts of the compounds of this invention include acidaddition salts which may, for example, be formed by mixing a solution ofthe compound according to the invention with a solution of apharmaceutically acceptable acid such as hydrochloric acid, sulphuricacid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid,acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid,carbonic acid or phosphoric acid. Furthermore, where the compounds ofthe invention carry an acidic moiety, suitable pharmaceuticallyacceptable salts thereof may include alkali metal salts, e.g. sodium orpotassium salts; alkaline earth metal salts, e.g. calcium or magnesiumsalts; and salts formed with suitable organic ligands, e.g. quaternaryammonium salts.

The present invention includes within its scope prodrugs of thecompounds of formula I above. In general, such prodrugs will befunctional derivatives of the compounds of formula I which are readilyconvertible it vivo into the required compound of formula I.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in Designs of Prodrugs,ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to the invention have at least oneasymmetric centre, they may accordingly exist as enantiomers. Where thecompounds according to the invention possess two or more asymmetriccentres, they may additionally exist as diastereoisomers. It is to beunderstood that all such isomers and mixtures thereof in any proportionare encompassed within the scope of the present invention.

Suitably, Y represents hydrogen or methyl, especially hydrogen.

Examples of suitable bicycloalkyl moieties for the group Z include thering systems of formula Za, Zb, Zc and Zd:

wherein R³ represents hydrogen, halogen or C₁₋₆ alkyl.

Particular values of R³ include hydrogen, fluoro and methyl, especiallyhydrogen.

Typical bicycloalkyl moieties for the group Z include the ring systemsof formula Za and Zb as depicted above. One particular bicycloalkylmoiety Z is represented by the ring system of formula Zb as depictedabove. Another particular bicycloalkyl moiety Z is represented by thering system of formula Za as depicted above.

Specific examples of the bicycloalkyl moiety Z includebicyclo[2.1.1]hex-1-yl and bicyclo[2.2.1]hept-1-yl. In one typicalembodiment, the group Z represents bicyclo[2.2.1]hept-1-yl. In anothertypical embodiment, the group Z represents bicyclo[2.1.1]hex-1-yl.

Examples of typical optional substituents on the group R¹ includemethyl, fluoro and methoxy.

Representative values of R¹ include cyclopropyl, phenyl, methylphenyl,fluorophenyl, difluorophenyl, methoxyphenyl, furyl, thienyl,methyl-thienyl and pyridinyl. Suitably, R¹ may represent unsubstitutedor monosubstituted phenyl. Specific values of R¹ include phenyl andfluorophenyl. More particularly, R¹ represents phenyl.

Suitable values for the substituent R² in the compounds according to theinvention include cyanomethyl, hydroxybutyl, cyclohexylmethyl,propargyl, pyrrolidinylcarbonylmethyl, benzyl, pyrazolylmethyl,isoxazolylmethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl,benzimidazolylmethyl, oxadiazolylmethyl, triazolylmethyl,tetrazolylmethyl, pyridinylmethyl, pyridazinylmethyl, pyrimidinylmethyl,pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl andquinoxalinylmethyl, any of which groups may be optionally substituted byone or more substituents. Typical values of R² include triazolylmethyland pyridinylmethyl, either of which groups may be optionallysubstituted.

Examples of suitable optional substituents on the group R² include C₁₋₆alkyl, aryl(C₁₋₆)alkyl, pyridyl(C₁₋₆)alkyl, halogen, halo(C₁₋₆)alkyl,cyano, cyano(C₁₋₆)alkyl, hydroxymethyl, C₁₋₆ alkoxy, C₃₋₇cycloalkyl(C₁₋₆)alkoxy, amino(C₁₋₆)alkyl, di(C₁₋₆)alkylamino(C₁₋₆)alkyl,di(C₁₋₆)alkylaminocarbonyl(C₁₋₆)alkyl, N-(C₁₋₆)alkylpiperidinyl,pyrrolidinyl(C₁₋₆)alkyl, (C₁₋₆)alkyl, morpholinyl(C₁₋₆)alkyl anddi(C₁₋₆)alkylmorpholinyl(C₁₋₆)alkyl.

Specific illustrations of particular substituents on the group R²include methyl, ethyl, n-propyl, benzyl, pyridinylmethyl, chloro,chloromethyl, cyano, cyanomethyl, hydroxymethyl, ethoxy,cyclopropylmethoxy, dimethylamtinomethyl, aminoethyl,dimethylaminoethyl, dimethylaminocarbonylmethyl, N-methylpiperidinyl,pyrrolidinylethyl, piperazinylethyl, morpholinylmethyl anddimethylmorpholinylmethyl, especially methyl.

Representative values of R² include cyanomethyl, hydroxybutyl,hydroxymethyl-cyclohexylmethyl, propargyl, dimethylaminomethyl-propargl,dimethylmorpholinylmethyl-propargyl, pyrrolidinylcarbonylmethyl,cyanobenzyl, hydroxymethyl-benzyl, pyrazolylmethyl,dimethyl-pyrazolylmethyl, methyl-isoxazolylmethyl, thiazolylmethyl,methyl-thiazolylmethyl, ethyl-thiazolylmethyl, methyl-thiazolylethyl,imidazolylmethyl, methyl-imidazolylmethyl, ethyl-imidazolylmethyl,benzyl-imidazolylmethyl, benzimidazolylmethyl, methyl-oxadiazolylmethyl,triazolylmethyl, methyl-triazolylmethyl, propyl-triazolylmethyl,benzyl-triazolylmethyl, pyridinylmethyl-triazolylmethyl,cyanomethyl-triazolylmethyl, dimethylaminomethyl-triazolylmethyl,aminoethyl-triazolylmethyl, dimethylaminoethyl-triazolylmethyl,dimethylaminocarbonylmethyl-triazolylmethyl,N-methylpiperidinyl-triazolylmethyl, pyrrolidinylethyl-triazolylmethyl,piperazinylethyl-triazolylmethyl, morpholinylethyl-triazolylmethyl,methyl-tetrazolylmethyl, pyridinylmethyl, methyl-pyridinylmethyl,dimethyl-pyridinylmethyl, ethoxy-pyridinylmethyl,cyclopropylmethoxy-pyridinylmethyl, pyridazinylmethyl,chloro-pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl,quinolinylmethyl, isoquinolinylmethyl and quinoxalinylmethyl.

Specific values of R² include methyl-triazolylmethyl, pyridinylmethyland methyl-pyridinylmethyl.

A favoured value of R² is methyl-triazolylmethyl.

A particular sub-class of compounds according to the invention isrepresented by the compounds of formula IIA, and salts and prodrugsthereof:

wherein

R¹ and R³ are as defined above;

m is 1 or 2, preferably 1; and

R¹² represents aryl or heteroaryl, either of which groups may beoptionally substituted.

Suitable values for R¹² include phenyl, pyrazolyl, isoxazolyl,thiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, triazolyl,tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl,isoquinolinyl and quinoxalinyl, any of which groups may be optionallysubstituted.

Particular values for R¹² include triazolyl and pyridinyl, either ofwhich groups may be optionally substituted.

Examples of typical substituents on the group R¹² include C₁₋₆, alkyl,aryl(C₁₋₆)alkyl, pyridyl(C₁₋₆)alkyl, halogen, cyano, cyano(C₁₋₆)alkyl,hydroxymethyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl(C₁₋₆)alkoxy,di(C₁₋₆)alkylamino(C₁₋₆)alkyl, amino(C₁₋₆)alkyl,di(C₁₋₆)alkylaminocarbonyl(C₁₋₆)alkyl, N-(C₁₋₆)alkylpiperidinyl,pyrrolidinyl(C₁₋₆)alkyl, piperazinyl(C₁₋₆)alkyl andmorpholinyl(C₁₋₆)alkyl.

Illustrative values of specific substituents on the group R¹² includemethyl, ethyl, n-propyl, benzyl, pyridinylmethyl, chloro, cyano,cyanomethyl, hydroxymethyl, ethoxy, cyclopropylmethoxy,dimethylaminomethyl, aminoethyl, dimethylaminoethyl,dimethylaminocarbonylmethyl, N-methylpiperidinyl, pyrrolidinylethyl,piperazinylethyl and morpholinylmethyl, especially methyl.

Particular values of R¹² include cyanophenyl, hydroxymethyl-phenyl,pyrazolyl, dimethyl-pyrazolyl, methyl-isoxazolyl, thiazolyl,methyl-thiazolyl, ethyl-thiazolyl, imidazolyl, methyl-imidazolyl,ethyl-imidazolyl, benzyl-imidazolyl, benzimidazolyl, methyl-oxadiazolyl,triazolyl, methyl-triazolyl, propyl-triazolyl, benzyl-triazolyl,pyridinylmethyl-triazolyl, cyanomethyl-triazolyl,dimethylaminomethyl-triazolyl, aminoethyl-triazolyl,dimethylaminoethyl-triazolyl, dimethylaminocarbonylmethyl-triazolyl,N-methylpiperidinyl-triazolyl, pyrrolidinylethyl-triazolyl,piperazinylethyl-triazolyl, morpholinylethyl-triazolyl,methyl-tetrazolyl, pyridinyl, methyl-pyridinyl, dimethyl-pyridinyl,ethoxy-pyridinyl, cyclopropylmethoxy-pyridinyl, pyridazinyl,chloro-pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyland quinoxalinyl.

Specific values of R¹² include methyl-triazolyl, pyridinyl andmethyl-pyridinyl.

A favoured value of R¹² is methyl-triazolyl.

A particular subset of the compounds of formula IIA above is representedby the compounds of formula IIB, and pharmaceutically acceptable saltsthereof:

wherein

R¹ and R³ are as defined above; and

R⁴ represents hydrogen or methyl.

In relation to formula IIB above, R¹ suitably represents phenyl.

Suitably, R⁴ represents methyl.

Another sub-class of compounds according to the invention is representedby the compounds of formula IIC, and salts and prodrugs thereof:

wherein R¹, R³ and R⁴ are as defined above.

In relation to formula IIC above, R¹ suitably represents fluorophenyl.

Specific compounds within the scope of the present invention include:

7-(bicyclo[2.2.1]hept-1-yl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine;

7-(bicyclo[2.2.1]hept-1-yl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine;

7-(bicyclo[2.2.1]hept-1-yl)-3-phenyl-6-(pyridin-2-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine;

7-(bicyclo[2.2.1]hept-1-yl)-6-(6-methylpyridin-2-ylmethoxy)-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine;

7-(bicyclo[2.2.1]hept-1-yl)-6-(3-methylpyridin-2-ylmethoxy)-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine;

7-(bicyclo[2.1.1]hex-1-yl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine;

7-(bicyclo[2.1.1]hex-1-yl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine;

and salts and prodrugs thereof.

Also provided by the present invention is a method for the treatmentand/or prevention of anxiety which comprises administering to a patientin need of such treatment an effective amount of a compound of formula Ias defined above or a pharmaceutically acceptable salt thereof or aprodrug thereof.

Further provided by the present invention is a method for the treatmentand/or prevention of convulsions (e.g. in a patient suffering fromepilepsy or a related disorder) which comprises administering to apatient in need of such treatment an effective amount of a compound offormula I as defined above or a pharmaceutically acceptable salt thereofor a prodrug thereof.

The binding affinity (K_(i)) of the compounds according to the presentinvention for the α3 subunit of the human GABA_(A) receptor isconveniently as measured in the assay described hereinbelow. The α3subunit binding affinity (K_(i)) of the compounds of the invention isideally 10 nM or less, preferably 2 nM or less, and more preferably 1 nMor less.

The compounds according to the present invention will ideally elicit atleast a 40%, preferably at least a 50%, and more preferably at least a60%, potentiation of the GABA EC₂₀ response in stably transfectedrecombinant cell lines expressing the α3 subunit of the human GABA_(A)receptor. Moreover, the compounds of the invention will ideally elicitat most a 30%, preferably at most a 20%, and more preferably at most a10%, potentiation of the GABA EC₂₀ response in stably transfectedrecombinant cell lines expressing the al subunit of the human GABA_(A)receptor.

The potentiation of the GABA EC₂₀ response in stably transfected celllines expressing the α3 and α1 subunits of the human GABA_(A) receptorcan conveniently be measured by procedures analogous to the protocoldescribed in Wafford et al., Mol. Pharmacol., 1996, 50, 670-678. Theprocedure will suitably be carried out utilising cultures of stablytransfected eukaryotic cells, typically of stably transfected mouse Ltk⁻fibroblast cells.

The compounds according to the present invention exhibit anxiolyticactivity, as may be demonstrated by a positive response in the elevatedplus maze and conditioned suppression of drinking tests (cf. Dawson etal., Psychopharmacology, 1995, 121, 109-117). Moreover, the compounds ofthe invention are substantially non-sedating, as may be confirmed by anappropriate result obtained from the response sensitivity(chain-pulling) test (cf. Bayley et al., J. Psychopharmacol., 1996, 10,206-213).

The compounds according to the present invention may also exhibitanticonvulsant activity. This can be demonstrated by the ability toblock pentylenetetrazole-induced seizures in rats and mice, following aprotocol analogous to that described by Bristow et al. in J. Pharmacol.Exp. Ther., 1996, 279, 492-501.

In order to elicit their behavioural effects, the compounds of theinvention will ideally be brain-penetrant; in other words, thesecompounds will be capable of crossing the so-called “blood-brainbarrier”. Preferably, the compounds of the invention will be capable ofexerting their beneficial therapeutic action following administration bythe oral route.

The invention also provides pharmaceutical compositions comprising oneor more compounds of this invention in association with apharmaceutically acceptable carrier. Preferably these compositions arein unit dosage forms such as tablets, pills, capsules, powders,granules, sterile parenteral solutions or suspensions, metered aerosolor liquid sprays, drops, ampoules, auto-injector devices orsuppositories; for oral, parenteral, intranasal, sublingual or rectaladministration, or for administration by inhalation or insufflation. Forpreparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a pharmaceutically acceptable saltthereof. When referring to these preformulation compositions ashomogeneous, it is meant that the active ingredient is dispersed evenlythroughout the composition so that the composition may be readilysubdivided into equally effective unit dosage forms such as tablets,pills and capsules. This solid preformulation composition is thensubdivided into unit dosage forms of the type described above containingfrom 0.1 to about 500 mg of the active ingredient of the presentinvention. Typical unit dosage forms contain from 1 to 100 mg, forexample 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. Thetablets or pills of the novel composition can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permits theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

In the treatment of anxiety, a suitable dosage level is about 0.01 to250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, andespecially about 0.05 to 5 mg/kg per day. The compounds may beadministered on a regimen of 1 to 4 times per day.

The compounds of formula I as defined above may be prepared by a processwhich comprises reacting a compound of formula III with a compound offormula IV:

wherein Y, Z, R¹ and R² are as defined above; and L¹ represents asuitable leaving group.

The leaving group L¹ is typically a halogen atom, especially chloro.

The reaction between compounds III and IV is conveniently effected bystirring the reactants in a suitable solvent, typicallyN,N-dimethyl-formamide, in the presence of a strong base such as sodiumhydride or lithium bis(trimethylsilyl)amide.

The intermediates of formula III above may be prepared by reacting acompound of formula V with a substantially equimolar amount of ahydrazine derivative of formula VI:

wherein Y, Z, R¹ and L¹ are as defined above, and L² represents asuitable leaving group; followed, if necessary, by separation of theresulting mixture of isomers by conventional means.

The leaving group L² is typically a halogen atom, especially chloro. Inthe intermediates of formula V, the leaving groups L¹ and L² may be thesame or different, but are suitably the same, preferably both chloro.

The reaction between compounds V and VI is conveniently effected byheating the reactants in the presence of a proton source such astriethylamine hydrochloride, typically at reflux in an inert solventsuch as xylene or 1,4-dioxane.

The reaction between compounds V and VI will, as indicated above,usually give rise to a mixture of isomeric products depending uponwhether the hydrazine derivative VI displaces the leaving group L¹ orL². Thus, in addition to the required product of formula III, theisomeric compound wherein the Y and Z moieties are reversed will usuallybe obtained to some extent. For this reason it will generally benecessary to separate the resulting mixture of isomers by conventionalmethods such as chromatography.

In another procedure, the compounds of formula I as defined above may beprepared by a process which comprises reacting a compound of formula VIIwith a compound of formula VIII:

wherein Y, Z, R¹ and R² are as defined above; and L³ represents asuitable leaving group.

The leaving group L³ is suitably a halogen atom, typically chloro orbromo.

The reaction between compounds VII and VIII is conveniently effected bystirring the reactants in a suitable solvent, typicallyN,N-dimethylformamide, in the presence of a strong base such as sodiumhydride.

The intermediates of formula VII above may conveniently be prepared byreacting a compound of formula III as defined above with an alkali metalhydroxide, e.g. sodium hydroxide. The reaction is conveniently effectedin an inert solvent such as aqueous 1,4-dioxane, ideally at the refluxtemperature of the solvent.

In a further procedure, the compounds of formula I as defined above maybe prepared by a process which comprises reacting a compound of formulaZ—CO₂H with a compound of formula IX:

wherein Y, Z, R¹ and R² are as defined above; in the presence of silvernitrate and ammonium persulphate.

The reaction is conveniently carried out under acidic conditions in asuitable solvent, for example using sulphuric acid in water or aqueousacetonitrile, typically at an elevated temperature.

Similarly, the intermediates of formula V above may be prepared byreacting a compound of formula Z—CO₂H with a compound of formula X:

wherein Y, Z, L¹ and L² are as defined above; in the presence of silvernitrate and ammonium persulphate; under conditions analogous to thosedescribed above for the reaction between Z—CO₂H and compound IX;followed, if necessary, by separation of any resulting mixture ofisomers by conventional means such as chromatography.

The intermediates of formula IX correspond to the compounds of formula Ias defined above wherein Z is hydrogen, and they may therefore beprepared by methods analogous to those described above for preparing thecorresponding compounds of formula I.

In a still further procedure, the compounds of formula I as definedabove may be prepared by a process which comprises reacting a compoundof formula XI with a compound of formula XII:

wherein Y, Z, R¹ and R² are as defined above, Alk represents a C₁₋₆alkyl group, typically n-butyl, and L⁴ represents a suitable leavinggroup; in the presence of a transition metal catalyst.

The leaving group L⁴ is suitably a halogen atom, e.g. bromo.

A suitable transition metal catalyst of use in the reaction betweencompounds XI and XII comprisesdichlorobis(triphenylphosphine)-palladium(II).

The reaction between compounds XI and XII is conveniently effected in aninert solvent such as N,N-dimethylformamide, typically at an elevatedtemperature.

The intermediates of formula XI may be prepared by reacting a compoundof formula IV as defined above with a compound of formula XIII:

wherein Y, Z, L¹ and L⁴ are as defined above; under conditions analogousto those described above for the reaction between compounds III and IV.

Where they are not commercially available, the starting materials offormula IV, VI, VIII, X, XII and XIII may be prepared by methodsanalogous to those described in the accompanying Examples, or bystandard methods well known from the art.

It will be understood that any compound of formula I initially obtainedfrom any of the above processes may, where appropriate, subsequently beelaborated into a further compound of formula I by techniques known fromthe art. For example, a compound of formula I initially obtained whereinR² is unsubstituted may be converted into a corresponding compoundwherein R² is substituted, typically by standard alkylation procedures,for example by treatment with a haloalkyl derivative in the presence ofsodium hydride and N,N-dimethylformamide, or with a hydroxyalkylderivative in the presence of triphenylphosphine and diethylazodicarboxylate. Furthermore, a compound of formula I initiallyobtained wherein R² represents cyano(C₁₋₆)alkyl may be converted intothe corresponding 3-substituted 1,2,4-triazol-5-yl(C₁₋₆)alkyl analogueby treatment with the appropriate acyl hydrazine derivative in thepresence of a base such as sodium methoxide. Similarly, a compound offormula I initially obtained wherein R² represents an optionallysubstituted propargyl moiety may be converted into the corresponding1,2,3-triazolylmethyl analogue by treatment with azide anion. A compoundof formula I initially obtained wherein the R² substituent issubstituted by a halogen atom, e.g. chloro, may be converted into thecorresponding compound wherein the R² substituent is substituted by adi(C₁₋₆)alkylamino moiety by treatment with the appropriatedi(C₁₋₆)alkylamine, typically with heating in a solvent such as1,4-dioxane in a sealed tube.

Where the above-described processes for the preparation of the compoundsaccording to the invention give rise to mixtures of stereoisomers, theseisomers may be separated by conventional techniques such as preparativechromatography. The novel compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The novel compound, may, for example, beresolved into their component enantiomers by standard techniques such aspreparative HPLC, or the formation of diastereomeric pairs by saltformation with an optically active acid, such as(−)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaricacid, followed by fractional crystallization and regeneration of thefree base. The novel compounds may also be resolved by formation ofdiastereomeric esters or amides, followed by chromatographic separationand removal of the chiral auxiliary.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

The following Examples illustrate the preparation of compounds accordingto the invention.

The compounds in accordance with this invention potently inhibit thebinding of [³H]-flumazenil to the benzodiazepine binding site of humanGABA_(A) receptors containing the α2 or α3 subunit stably expressed inLtk⁻ cells.

Reagents

Phosphate buffered saline (PBS).

Assay buffer: 10 mM KH₂PO₄, 100 mM KCl, pH 7.4 at room temperature.

[³H]-Flumazenil (18 nM for α1β3γ2 cells; 18 nM for α2β3γ2 cells; 10 nMfor α3β3γ2 cells) in assay buffer.

Flunitrazepam 100 μM in assay buffer.

Cells resuspended in assay buffer (1 tray to 10 ml).

Harvesting Cells

Supernatant is removed from cells. PBS (approximately 20 ml) is added.The cells are scraped and placed in a 50 ml centrifuge tube. Theprocedure is repeated with a further 10 ml of PBS to ensure that most ofthe cells are removed. The cells are pelleted by centrifuging for 20 minat 3000 rpm in a benchtop centrifuge, and then frozen if desired. Thepellets are resuspended in 10 ml of buffer per tray (25 cm×25 cm) ofcells.

Assay

Can be carried out in deep 96-well plates or in tubes. Each tubecontains:

300 μl of assay buffer.

50 μl of [³H]-flumazenil (final concentration for α1 β3γ2: 1.8 nM; forα2β3γ2: 1.8 nM; for α3β3γ2: 1.0 nM).

50 μl of buffer or solvent carrier (e.g. 10% DMSO) if compounds aredissolved in 10% DMSO (total); test compound or flunitrazepam (todetermine non-specific binding), 10 μM final concentration.

100 μl of cells.

Assays are incubated for 1 hour at 40° C., then filtered using either aTomtec or Brandel cell harvester onto GF/B filters followed by 3×3 mlwashes with ice cold assay buffer. Filters are dried and counted byliquid scintillation counting. Expected values for total binding are3000-4000 dpm for total counts and less than 200 dpm for non-specificbinding if using liquid scintillation counting, or 1500-2000 dpm fortotal counts and less than 200 dpm for non-specific binding if countingwith meltilex solid scintillant. Binding parameters are determined bynon-linear least squares regression analysis, from which the inhibitionconstant K_(i) can be calculated for each test compound.

The compounds of the accompanying Examples were tested in the aboveassay, and all were found to possess a K_(i) value for displacement of[³H]-flumazenil from the α2 and/or α3 subunit of the human GABA_(A)receptor of 100 nM or less.

EXAMPLE 17-(Bicyclo[2.2.1]hept-1-yl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4-triazolo[4,3-b]pyridazinea) 4-(Bicyclo[2.2.1]hept-1-yl)-3,6-dichloropyridazine

Concentrated sulphuric acid (2.17 ml, 40 mM) was added carefully to asuspension of 3,6-dichloropyridazine (2.11 g, 14.3 mM) in water (50 ml).This mixture was then heated to 70° C. andbicyclo[2.2.1]heptane-1-carboxylic acid (Org. Synth., 59, 85; 2.0 g,14.3 mM) was added. After ten minutes a solution of silver nitrate (0.48g, 2.8 mM) in water (5 ml) was added dropwise over two minutes. Asolution of ammonium persulphate (9.8 g, 43 mM) in water (20 ml) wasadded over 20 minutes. The reaction was heated at 70° C. for a further40 minutes and then allowed to cool to room temperature. The mixture waspoured onto ice and basified with concentrated aqueous ammonia; thetemperature was kept below 10° C. by addition of more ice. The aqueousphase was extracted with dichloromethane (3×200 ml) and the combinedextracts were dried (MgSO₄), filtered and evaporated to give the crudeproduct, which was purified by column chromatography using ethylacetate/hexane mixtures as the eluent to give the title compound (3.4g). ¹H NMR (250 MHz, CDCl₃) δ1.49-2.00 (8H, m), 2.17 (2H, m), 2.43 (1H,m), 7.45 (1H, s); MS (ES⁺) m/e 244 [MH]⁺.

b)7-(Bicyclo[2.2.1]hept-1-yl)-6-chloro-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine

A mixture of 4-(bicyclo[2.2.1]hept-1-yl)-3,6-dichloropyridazine (1 g,4.1 mM), benzoic hydrazide (0.84 g, 6.2 mM) and triethylaminehydrochloride (0.85 g, 6.2 mM) in p-xylene (80 ml) was heated at refluxfor 18 hours, after which time more benzoic hydrazide (0.28 g, 2 mM) andtriethylamine hydrochloride (0.28 g, 2 mM) were added and the reactionheated at reflux for a further 3 hours. The mixture was allowed to cool,then placed directly onto silica gel for purification by columnchromatography using ethyl acetate/hexane mixtures as the eluent. Thisyielded the title compound (0.38 g, lower R_(f) of the two isomericproducts). ¹H NMR (250 MHz, CDCl₃) δ1.55-2.06 (8H, m), 2.22 (2H, m),2.44 (1H, m), 7.25 (3H, m), 8.13 (1H, s), 8.45 (2H, m); MS (ES⁺) m/e 244[MH]⁺.

c)7-(Bicyclo[2.2.1]hept-1-yl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine

To a solution of7-(bicyclo[2.2.1]hept-1-yl)-6-chloro-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine(0.125 g, 0.39 mM) and (2-methyl-2H-1,2,4-triazol-3-yl)methanol (0.08 g,0.47 mM; prepared using the conditions described in EP-A-421210) inN,N-dimethylformamide (20 ml) was added sodium hydride (0.015 g of a 60%dispersion in oil, 0.47 mM eq) and the reaction mixture was stirred atroom temperature for 3 hours. Water was added until the solution becamecloudy and after stirring for a further 15 minutes a solid was collectedby filtration. This solid was recrystallised from ethylacetate-dichloromethane to give the required product (0.048 g,m.p.=244-246° C.). ¹H NMR (360 MHz, DMSO) δ1.39 (2H, m), 1.67-1.84 (8H,m), 2.30 (1H, m), 3.93 (3H, s), 5.70 (2H, s), 7.52-7.62 (3H, m), 8.00(1H, s), 8.35 (1H, s), 8.38 (2H, m); (Regiochemistry was establishedusing nOe data). MS (ES⁺) m/e 402 [MH]⁺. Anal. Found C, 65.71; H, 5.65;N, 24.07. C₂₂H₂₃N₇O requires C, 65.82; H, 5.77; N, 24.42%.

EXAMPLE 27-(Bicyclo[2.2.]hept-1-yl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine

This compound was prepared using the procedure described in Example 1step c with (1-methyl-1H-1,2,4-triazol-3-yl)methanol (prepared using theconditions described in EP-A-421210) used instead of(2-methyl-2H-1,2,4-triazol-3-yl)methanol. Data for the title compound:m.p.=218-220° C.; ¹H NMR (360 MHz, DMSO) δ1.39 (2H, m), 1.68-1.90 (8H,m), 2.31 (1H, m), 3.88 (3H, s), 5.51 (2H, s), 7.52-7.63 (3H, m), 8.09(1H, s), 8.44 (2H, m), 8.56 (1H, s); MS (ES⁺) m/e 402 [MH]⁺. Anal. FoundC, 65.65; H, 5.58; N, 24.22. C₂₂H₂₃N₇O requires C, 65.82; H, 5.77; N,24.42%.

EXAMPLE 37-(Bicyclo[2.2.1]hept-1-yl)-3-phenyl-6-(pyridin-2-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine

To a solution of7-(bicyclo[2.2.1]hept-1-yl)-6-chloro-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine(0.08 g, 0.25 mM, Example 1, step b) and 2-pyridylcarbinol (0.06 ml, 0.5mM) in N,N-dimethylformamide (2 ml) under nitrogen was added lithiumbis(trimethylsilyl)amide as a 1 mol solution in hexanes (0.375 ml). Thereaction was stirred for 3 hours. Water was added until the solutionbecame cloudy and after stirring for a further 15 minutes a solid wascollected by filtration. This solid was recrystallised from ethylacetate-hexane to give the required product (0.050 g, m.p.=166-168° C.).¹H NMR (360 MHz, DMSO) δ1.55 (2H, m), 1.91 (4H, m), 1.97 (2H, m), 2.13(2H, m), 2.49 (1H, m), 5.77 (2H, s), 7.54 (1H, m), 7.69 (4H, s), 8.00(1H, t, J=7.6 Hz), 8.28 (1H, s), 8.34 (2H, dd, J=7.6 and 1.5 Hz), 8.80(1H, m); MS (ES⁺) m/e 398 [MH]⁺. Anal. Found C, 72.16; H, 5.59; N,17.41. C₂₄H₂₃N₅O. 0.1H₂O requires C, 72.20; H, 5.86; N, 17.54%.

EXAMPLE 4 7-(Bicyclo[2.2.1]hept-1-yl)-6-(6-methylpyridin-2-ylmethoxy)-3-phenyl- 1,2,4-triazolo[4,3-b]pyridazine

This compound was prepared using the procedure described in Example 3with 6-methyl-2-pyridylcarbinol used instead of 2-pyridylcarbinol. Datafor the title compound: m.p.=162-164° C.; ¹H NMR (360 MHz, DMSO) δ1.66(2H, m), 1.99-2.13 (8H, m), 2.59 (1H, m), 2.22 (3H, s), 5.93 (2H, s),7.62 (1H, m), 7.89 (3H, s), 8.00 (1H, d, J=7.4 Hz), 8.40 (1H, s), 8.61(2H, dd, J=7.4 and 1.5 Hz), 8.71 (1H, m); MS (ES⁺) m/e 412 [MH]⁺. Anal.Found C, 73.15; H, 5.97; N, 16.95. C₂₅H₂₅N₅O requires C, 72.97; H, 6.12;N, 17.02%.

EXAMPLE 57-(Bicyclo[2.2.1]hept-1-yl)-6-(3-methylpyridin-2-ylmethoxy)-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine

This compound was prepared using the procedure described in Example 3with 3-methyl-2-pyridylcarbinol used instead of 2-pyridylcarbinol. Datafor the title compound: m.p.=214-216° C.; ¹H NMR (360 MHz, DMSO) δ1.39(2H, m), 1.73-1.97 (8H, m), 2.32 (1H, m), 2.49 (3H, s), 5.55 (2H, s),7.20 (2H, m), 7.53 (3H, s), 7.73 (1H, m), 8.09 (1H, s) 8.28 (2H, dd,J=7.4 and 1.5 Hz); MS (ES⁺) m/e 412 [MH]⁺. Anal. Found C, 73.10; H,6.01; N, 17.02. C₂₅H₂₅N₅O requires C, 72.97; H, 6.12; N, 17.02%.

EXAMPLE 67-(Bicyclo[2.1.1]hex1-yl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine

This compound was prepared using the procedure described in Example 1a-cwith bicyclo[2.1.1]hexane-1-carboxylic acid used instead ofbicyclo[2.2.1]heptane-1-carboxylic acid (Org. Prep. & Procedures Int.,1980, 12, 357-360), and 2-fluorobenzhydrazide instead of benzoichydrazide. Data for the title compound: m.p.=198-200° C.; ¹H NMR (360MHz, DMSO) δ1.55 (2H, m), 1.78-1.85 (6H, m), 2.57 (1H, m), 3.18 (3H, s),5.47 (2H, s), 7.24-7.37 (2H, m), 7.57 (1H, m), 7.77 (1H, s), 7.82-7.88(2H, m); MS (ES⁺) m/e 406 [MH]⁺. Anal. Found C, 62.24; H, 4.91; N,24.08. C₂₁H₂₀FN₇O requires C, 62.21; H, 4.97; N, 24.18%.

EXAMPLE 77-(Bicyclo[2.1.1]hex-1-yl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine

This compound was prepared using the procedure described in Example 6with (1-methyl-1H-1,2,4-triazol-3-yl)methanol (prepared using theconditions described in EP-A-421210) used instead of(2-methyl-2H-1,2,4-triazol-3-yl)methanol. Data for the title compound:m.p.=170-172° C.; ¹H NMR (360 MHz, DMSO) δ1.58 (2H, m), 1.79-1.92 (6H,m), 2.54 (1H, m), 3.92 (3H, s), 5.39 (2H, s), 7.23-7.34 (2H, m), 7.53(1H, m), 7.73 (1H, s), 7.92-7.97 (2H, m), 8.02 (1H, s); MS (ES⁺) m/e 406[MH]⁺. Anal. Found C, 61.89; H, 4.70; N, 23.68. C₂₁H₂₀FN₇O.0.2 H₂Orequires C, 61.66; H, 5.03; N, 23.97%.

What is claimed is:
 1. A compound of formula I, or a salt or prodrugthereof:

wherein Y represents hydrogen or C₁₋₆alkyl; Z represents aC₆₋₈bicycloalkyl moiety optionally substituted with one or twoindependent C₁₋₆alkyl, phenyl(C₁₋₆)alkyl, naphthyl(C₁₋₆)alkyl, halogen,cyano, hydroxy, hydroxymethyl, C₁₋₆alkoxy or C₃₋₇cycloalkyl(C₁₋₆)alkoxysubstituents; R¹ represents C₃₋₇cycloalkyl, phenyl, furyl, thienyl orpyridinyl, any of which groups may be optionally substituted with one ortwo independent C₁₋₆alkyl, phenyl(C₁₋₆)alkyl, naphthyl(C₁₋₆)alkyl,halogen, cyano, hydroxy, hydroxymethyl, C₁₋₆alkoxy orC₃₋₇cycloalkyl(C₁₋₆)alkoxy substituents; and R² representscyano(C₁₋₆)alkyl, C₃₋₇cycloalkyl(C₁₋₆)alkyl, propargyl,azetidinylcarbonyl(C₁₋₆)alkyl, pyrrolidinylcarbonyl(C₁₋₆)alkyl,piperidinylcarbonyl(C₁₋₆)alkyl, piperazinylcarbonyl(C₁₋₆)alkyl,morpholinylcarbonyl(C₁₋₆)alkyl, thiomorpholinylcarbonyl(C₁₋₆)alkyl,phenyl(C₁₋₆)alkyl, naphthyl(C₁₋₆)alkyl, pyridinyl(C₁₋₆)alkyl,quinolinyl(C₁₋₆)alkyl, isoquinolinyl(C₁₋₆)alkyl, pyridazinyl(C₁₋₆)alkyl,pyrimidinyl(C₁₋₆)alkyl, pyrazinyl(C₁₋₆)alkyl, quinoxalinyl(C₁₋₆)alkyl,furyl(C₁₋₆)alkyl, benzofuryl(C₁₋₆)alkyl, dibenzofuryl(C₁₋₆)alkyl,thienyl(C₁₋₆)alkyl, benzthienyl(C₁₋₆)alkyl, pyrrolyl(C₁₋₆)alkyl,indolyl(C₁₋₆)alkyl, pyrazolyl(C₁₋₆)alkyl, indazolyl(C₁₋₆)alkyl,oxazolyl(C₁₋₆)alkyl, isoxazolyl(C₁₋₆)alkyl, thiazolyl(C₁₋₆)alkyl,isothiazolyl(C₁₋₆)alkyl, imidazolyl(C₁₋₆)alkyl,benzimidazolyl(C₁₋₆)alkyl, oxadiazolyl(C₁₋₆)alkyl,thiadiazolyl(C₁₋₆)alkyl, triazolyl(C₁₋₆)alkyl, or tetrazolyl(C₁₋₆)alkyl,any of which groups may be optionally substituted with one or twoindependent C₁₋₆alkyl, phenyl(C₁₋₆)alkyl, naphthyl(C₁₋₆)alkyl, halogen,cyano, hydroxy, hydroxymethyl, C₁₋₆alkoxy or C₃₋₇cycloalkyl(C₁₋₆)alkoxysubstituents.
 2. A compound as claimed in claim 1 wherein Z represents aring system of formula Za, Zb, Zc or Zd:

wherein R³ represents hydrogen, halogen or C₁₋₆ alkyl.
 3. A compound asclaimed in claim 2 represented by formula IIA, and salts thereof:

wherein m is 1 or 2; and R¹² represents phenyl, naphthyl, pyridinyl,quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl,quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl,pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl,thiadiazolyl, triazolyl, or tetrazolyl, optionally substituted with oneor two independent C₁₋₆alkyl, phenyl(C₁₋₆)alkyl, naphthyl(C₁₋₆)alkyl,halogen, cyano, hydroxymethyl, C₁₋₆alkoxy or C₃₋₇cycloalkyl(C₁₋₆)alkoxysubstituents.
 4. A compound as claimed in claim 3 represented by formulaIIB, and pharmaceutically acceptable salts thereof:

wherein R¹ is as defined in claim 1; R³ is as defined in claim 2; and R⁴represents hydrogen or methyl.
 5. A compound as claimed in claim 2represented by formula IIC, and salts thereof:

wherein R⁴ represents hydrogen or methyl.
 6. A compound selected from:7-(bicyclo[2.2.1]hept-1-yl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine;7-(bicyclo[2.2.1]hept-1-yl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine;7-(bicyclo[2.2.1]hept-1-yl)-3-phenyl-6-(pyridin-2-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine;7-(bicyclo[2.2.1]hept-1-yl)-6-(6-methylpyridin-2-ylmethoxy)-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine;7-(bicyclo[2.2.1]hept-1-yl)-6-(3-methylpyridin-2-ylmethoxy)-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine;7-(bicyclo[2.2.1]hex-1-yl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine;7-(bicyclo[2.2.1]hex-1-yl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine;and salts thereof.
 7. A pharmaceutical composition comprising a compoundof formula I as defined in claim 1 or a pharmaceutically acceptable saltthereof in association with a pharmaceutically acceptable carrier.
 8. Aprocess for the preparation of a compound as claimed in claim 1, whichcomprises: (A) reacting a compound of formula III with a compound offormula IV:

wherein Y, Z, R¹ and R² are as defined in claim 1, and L¹ represents asuitable leaving group; or (B) reacting a compound of formula VII with acompound of formula VIII:

wherein Y, Z, R¹ and R² are as defined in claim 1, and L³ represents asuitable leaving group; or (C) reacting a compound of formula Z—CO₂Hwith a compound of formula IX:

wherein Y, Z, R¹ and R² are as defined in claim 1; in the presence ofsilver nitrate and ammonium persulphate; or (D) reacting a compound offormula XI with a compound of formula XII:

wherein Y, Z, R¹ and R² are as defined in claim 1, Alk represents aC₁₋₆alkyl group, and L⁴ represents a suitable leaving group; in thepresence of a transition metal catalyst.
 9. A method for the treatmentof anxiety which comprises administering to a patient in need of suchtreatment an effective amount of a compound of formula I as defined inclaim 1, or a pharmaceutically acceptable salt thereof.
 10. A method forthe treatment and/or prevention of convulsions which comprisesadministering to a patient in need of such treatment an effective amountof a compound of formula I as defined in claim 1, or a pharmaceuticallyacceptable salt thereof.